Totally Bioresorbable Cardiovascular Stents Prepared From L-lactide, Trimethylene Carbonate And Glycolide Terpolymers

In this work, high molar mass terpolymers based on L-lactide (LLA), trimethylene carbonate (TMC) and glycolide (GA) are synthesized. The thermal and mechanical properties, enzymatic and hydrolytic degradation behaviors, and the biocompatibility of PLLA-TMC-GA terpolymers are investigated, in comparison with the corresponding PLLA-TMC copolymers as well as PLLA and PTMC homopolymers. Furthermore, a stent prototype is manufactured by a CNC engraving machine. The main contents are shown as follows.1.A series of PLLA-TMC-GA terpolymers with different chain microstructures are synthesized by ring-opening polymerization of LLA, TMC and GA, using stannous (II) octoate as initiator. The corresponding PLLA-TMC copolymers with different compositions and a PLLA and PTMC homopolymer are also obtained for comparison. The chain microstructure of the PLLA-TMC-GA terpolymers is examined by means of both 1H and 13C NMR analysis. The results show that the incorporation of GA moiety instead of TMC moiety leads to shorter average LLA block length. Meanwhile, the relationship between average LLA block length (lLLA) and TMC or GA content follows an exponential decay model.2. The relationship between the chain microstructure and property of the terpolymers is discussed. The thermal and mechanical properties are significantly affected by both the composition and the chain microstructure. Incorporation of TMC and GA units strongly decreases the crystallinity of PLLA-TMC-GA terpolymers due to their more random microstructure as evidenced by 13C NMR. The crystallinity of PLLA-based copolymers mainly depends on the average LLA block length. Meanwhile, the toughness of the terpolymers is greatly improved, with only a slight loss of tensile strength. These findings are of major importance as the microblock structure of copolymer chains could be precisely controlled by varying the comonomer composition, and thus can be usefully applied to predict the crystallization and mechanical properties for the development of bioresorbable cardiovascular stents.3. Solution cast films of the selected terpolymers are allowed to degrade at 37℃ in pH 8.5 Tris buffer using proteinase K. The results show that the enzymatic degradation rate of PLLA-TMC-GA terpolymers with predominant LLA component is affected by both the average LLA block length and crystallinity. A shorter average LLA block length results in lower crystallinity, which will lead to faster degradation. However, too short average LLA block length (i. e.lLLA≤4.0) can retard the degradation process. The composition of the copolymers remains unchanged during degradation. In contrast, the molar mass decreases due to hydrolytic chain cleavage in the bulk. Similarly, thermal property changes are observed with increase of the melting temperature and melting enthalpy in most cases. SEM observation strongly supports a surface erosion mechanism.4. The hydrolytic degradation of the terpolymers is performed in pH 7.4 PBS at 37℃. PLLA-TMC-GA terpolymers degrade faster than PLLA-TMC copolymers and PLLA homopolymer due to more random chain structure and the presence of GA units. The crystallization ability of polymers increases due to the impact of plasticization of water and the decreasing of molar mass. However, too low malar mass (i. e.<10,000) results in a decrease of crystallinity. Compositional changes indicate the hydrolytic degradation occurs in three steps:the fast degradation of GA units in the amorphous and unperfect crystallization regions, followed by LLA units degrade in the same regions, and finally the LLA and GA units degrade with the degrdation of crystallization region.5. The biocompatibility of the terpolymers is evaluated from the aspects of cytocompatibility, hemocompatibility and immunocompatibility. The results reveal that the polymers present good cytocompatibility, no significant hemolysis, low degree of activation with few adhered platelets and excellent anti-coagulation properties. Moreover, no significant increase in the release of cytokines is detected. It is concluded that these polymers, in particular PLLA-TMC-GA terpolymer present outstanding biocompatibility.6. Totally bioresorbable poly[(L-lactide)-co-glycolide] (PLGA) fibers are used to reinforce the PLLA-TMC-GA terpolymers. The results show that the composite with plasma-treated PLGA fibers exhibits improved tensile strength and modulus. The mass loss rate of the composite is lower than that of the neat terpolymer during proteinase K-catalyzed degradation due to the presence of PLGA fibers which are non-degradable by proteinase K. However, the composite shows much faster molar mass loss rate than the neat terpolymer because the rapid hydrolytic degradation of PLGA fibers speeds up the degradation of the matrix by internal autocatalysis during both enzymatic and hydrolytic degradation.7. A mini-tube is fabricated using a single-screw extruder, and a stent prototype is successfully manufactured from a terpolymer by a CNC engraving machine.These polymeric bioresorbable stents are expected to provide radial support for vessels for 6-9 months and totally degrade in 1-2 years, thus avoiding later inflammation and restenosis and leaving patients with a healed vessel free of a permanent metal implant.In conclusion, compared with PLLA homopolymer and PLLA-TMC copolymers, the high molar mass PLLA-TMC-GA terpolymers exhibit higher toughness, appropriate degradation rate, better biocompatibility and excellent processing performance, and thus are promising as bioresorbable cardiovascular stent materials.